Clinical Trials /

Pembrolizumab In Combination With Debio 1143 In Pancreatic and Colorectal Advanced/Metastatic Adenocarcinoma

NCT03871959

Description:

This trial is a Phase I study to be conducted in patients with non-MSI-high advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer (CRC) and is divided in two Parts. - Dose escalation Part :To determine the Maximum Tolerated Dose (MTD) and the Recommended Dose for Phase 2 (RP2D) of Debio1143 when combined with a fixed dose of Pembrolizumab. - Extension Part: To evaluate preliminary efficacy data of the proposed combination.

Related Conditions:
  • Colorectal Carcinoma
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab In Combination With Debio 1143 In Pancreatic and Colorectal Advanced/Metastatic Adenocarcinoma
  • Official Title: CATRIPCA - A Phase I Study of PD1 Monoclonal Antibody (Pembrolizumab) In Combination With a IAP Antagonist (Debio 1143) In (Exocrine) Pancreatic And Colorectal Non MSI-high Advanced/Metastatic Adenocarcinoma.

Clinical Trial IDs

  • ORG STUDY ID: ET16-023 CATRIPCA
  • NCT ID: NCT03871959

Conditions

  • Adenocarcinoma of the Pancreas
  • Adenocarcinoma of the Colon
  • Adenocarcinoma of the Rectum

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaPembrolizumab + Debio 1143
DEBIO1143Pembrolizumab + Debio 1143

Purpose

This trial is a Phase I study to be conducted in patients with non-MSI-high advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer (CRC) and is divided in two Parts. - Dose escalation Part :To determine the Maximum Tolerated Dose (MTD) and the Recommended Dose for Phase 2 (RP2D) of Debio1143 when combined with a fixed dose of Pembrolizumab. - Extension Part: To evaluate preliminary efficacy data of the proposed combination.

Detailed Description

      All patient wil receive a combinaison of Pembrolizumab and Debio 1143. Pembrolizumab is a
      potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype
      designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

      Debio 1143 is an investigational, oral monovalent second mitochondrial-derived activator of
      caspases (SMAC) mimetic designed to promote programmed cell death (apoptosis) in tumor cells
      and anti-tumour immunity. By antagonizing the activity of inhibitor of apoptosis proteins
      (IAPs (X-linked IAP [XIAP], cellular IAP 1 [cIAP1], cellular IAP 2 [cIAP2] and
      melanoma-linked IAP [ML-IAP])), Smac mimetics are an interesting treatment approach for
      cancer that may foster better tumor responses to chemo/radiotherapy- and/or immuno-therapy.

      A Dose escalation part (n= up to 18 patients ) aiming to define the Maximum Tolerated Dose
      and the the Recommended Dose for Phase 2 of the proposed combination. A classical 3+3 design
      will be used with a fixed dose of Pembrolizumab (200 mg, intravenous , to be administered on
      Day 1 of every 3-week cycle i.e. Q3W) and 3 escalating dose level of Debio 1143 administered
      daily for 14 days over a 21-day cycle period.

      There will be a 24-hour delay between the first and subsequent patients enrolled in each DL
      cohort to maximize the safety of enrolled patients.

      An extension part (n=28 patients: 14 patients per cohort) aiming to evaluate the clinical
      activity of the proposed combination.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + Debio 1143ExperimentalPembrolizumab : 200 mg, intravenous (IV), to be administered on Day 1 of every 3-week cycle i.e. Q3W. Debio 1143 : 3 escalating dose level (100 mg, 150 mg, 200 mg) administered daily for 14 days over a 21-day cycle period.
  • Pembrolizumab
  • DEBIO1143

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female patients aged of at least 18 years on day of signing informed consent.

          -  Histologically-confirmed diagnosis of Stage III or IV (according to the current
             version of the American Joint Committee on Cancer (AJCC)) of PDAC or Stage IV CRC.

          -  Previous treatment in the metastatic / advanced stage: PDAC: at least one line of
             chemotherapy and CRC: at least one line of chemotherapy containing 5-FU, oxaliplatin,
             irinotecan, plus bevacizumab if patient is eligible, plus anti-EGFR if CRC with RAS
             wild-type.

          -  Documented radiological disease progression as per RECIST V1.1 at time of inclusion.

          -  At least one measurable lesion according to RECIST v1.1.

          -  Presence of at least one tumor lesion with a diameter ≥10 mm, visible by medical
             imaging and accessible to repeatable percutaneous or endoscopic sampling that permit
             core needle biopsy without unacceptable risk and suitable for retrieval of a minimum
             of three cores, but ideally 4 cores.

          -  Availability of a representative formalin-fixed and paraffin-embedded (FFPE) primary
             and/or metastatic tumor tissue with an associated pathology report.

          -  ECOG Performance Status (PS) 0 or 1 (See Appendix 1).

          -  Life expectancy of at least 12 weeks.

          -  Demonstrate adequate organ function as defined in table below, all screening
             laboratory tests should be performed within 7 days prior C1D1.

          -  Able to swallow and retain orally administered medication.

          -  Minimal wash-out period for the following treatments (= minimal delay between the last
             dose of these treatments and C1D1): Chemotherapy, tyrosine kinase inhibitor or
             radiation therapy : 2 weeks; Immunosuppressive medication: 4 weeks, with the
             exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at
             physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent
             corticosteroid; Any investigational agents: 5 half-lives of the investigation agent
             with a minimum of 2 weeks; Monoclonal antibodies: 4 weeks; Major surgical procedure,
             open biopsy (excluding skin cancer resection or screening biopsy), or significant
             traumatic injury : 2 weeks; Live vaccines : 4 weeks.

          -  Women of child-bearing potential must have a negative serum pregnancy test at
             Screening and must agree to use 2 effective forms of contraception from the time of
             the negative pregnancy test up to 120 days after the last dose of study drugs.

          -  Fertile men must agree to use contraceptive measures up to 120 days after the last
             dose of study drugs.

          -  Patients who understand, sign, and date the written voluntary informed consent form at
             the screening visit prior to any protocol-specific procedures. Patient should be able
             and willing to comply with study visits and procedures as per protocol.

          -  Patients must be covered by a medical insurance.

        Exclusion Criteria:

          -  Patients amenable to therapy with curative intent.

          -  Patient participating to another clinical trial with a medicinal product.

          -  Patients with microsatellite instability (MSI)-high or mismatch repair MMR-deficient
             tumors.

          -  Patients who have not recovered from adverse events (i.e. > Grade 1 according to NCI
             CTCAE v5.0 See Appendix 5) due to prior treatment with anti-cancer agents with
             exception of Grade 2 neuropathy, any Grade alopecia or lab values presented in
             criteria I10.

          -  Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTL-A4
             and any ICIs or IAP inhibitors.

          -  Patients who have a known additional malignancy that is progressing or requires active
             treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
             carcinoma of the skin, or in situ cervical cancer that has undergone potentially
             curative therapy.

          -  Patients with known active central nervous system (CNS) metastases and/or
             carcinomatous meningitis. Patients with previously treated brain metastases may
             participate provided they are stable (without evidence of progression by imaging for
             at least four weeks prior to C1D1 and any neurologic symptoms have returned to
             baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids (at doses higher than 10 mg/d of methylprednisolone or equivalent) for at
             least 4 weeks prior C1D1.

          -  Patients with a history of autoimmune disease requiring systemic treatment within the
             past 3 months or a documented history of clinically severe autoimmune disease, or a
             syndrome that requires systemic steroids (at doses higher than 10 mg/d of
             methylprednisolone or equivalent) or immunosuppressive agents.

          -  Patients with history of (non-infectious) pneumonitis that required steroids, evidence
             of interstitial lung disease or active, non-infectious pneumonitis.

          -  Patients with an evidence of active infection requiring systemic therapy.

          -  Patients with a history or current evidence of any condition, therapy, or laboratory
             abnormality that might confound the results of the trial, interfere with the patient's
             participation for the full duration of the trial.

          -  Patients with a history of uncontrolled or symptomatic, clinically significant
             cardiovascular disease : stroke, myocardial infarction, angina pectoris, arrhythmias,
             congestive heart failure (NYHA Class >2), or myocarditis within 6 months prior to
             first study drug administration.

          -  Patient with a history of organ transplant including stem cell allograft.

          -  Patients receiving or to be treated during the treatment period with one of the
             following forbidden treatment: Any anti-cancer systemic chemotherapy, targeted therapy
             or biological therapy including any immunotherapy not mentioned in this protocol; Any
             investigational agents other than Debio-1143; Radiation therapy; Live vaccines, Major
             surgery; Corticosteroids for any purpose other than to modulate symptoms from an event
             of clinical interest of suspected immunologic etiology. The use of physiologic doses
             of corticosteroids may be approved after consultation with the sponsor; Strong P-gp
             inhibitors or inducers.

          -  Patients with hypersensitivity to Pembrolizumab or any of its excipients.

          -  Patients with a known history of active TB (Bacillus Tuberculosis).

          -  Patients with : Active hepatitis B (chronic or acute; defined as having a positive
             hepatitis B surface antigen [HBsAg] test at screening), or Active hepatitis C.
             Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is
             negative for HCV RNA, or HIV infection.

          -  Patients with known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Patients who are pregnant or breastfeeding, or expecting to conceive or father
             children within the projected duration of the trial, starting with the screening visit
             through 120 days after the last dose of trial treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:21 days
Safety Issue:
Description:To determine the Maximum Tolerated Dose of Debio1143 when combined with a fixed dose of Pembrolizumab.

Secondary Outcome Measures

Measure:Duration of response
Time Frame:Up to 2 years
Safety Issue:
Description:The duration of response will be measured from the time of first documented response (Complete Response or Partial Response as per RECIST V1.1) until the first documented disease progression or death due to underlying cancer, and censored at the date of the last available tumor assessment.
Measure:Clinical Benefit Rate
Time Frame:12 weeks
Safety Issue:
Description:The Clinical Benefit Rate will be defined as the proportion of patients with Complete Response, Partial Response or stable disease according to RECIST V1.1.
Measure:Tumor-response efficacy 1
Time Frame:Up to 2 years
Safety Issue:
Description:The tumor-response efficacy endpoints described above will be evaluated by investigator-assessed RECIST v1.1 (Eisenhauer et al. E J Cancer 2009).
Measure:Tumor-response efficacy 2
Time Frame:Up to 2 years
Safety Issue:
Description:The tumor-response efficacy endpoints described above will be evaluated by modified criteria for immunotherapies iRECIST (Seymour et al. Lancet Oncol 2017).
Measure:Progression-Free Survival
Time Frame:Up to 2 years
Safety Issue:
Description:Progression-Free Survival (PFS) will be measured from the C1D1 until the date of event defined as the first documented progression or death from any cause. Patients with no event at the time of the analysis will be censored at the date of the last available tumor assessment.
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Overall survival (OS) will measured from C1D1 to the date of death from any cause. Patients who are alive at the time of analysis will be censored at the date of the last contact.
Measure:Assessment of safety will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTCAE v5.0) grade
Time Frame:Up to 2 years
Safety Issue:
Description:The assessment of safety will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTCAE v5.0) grade.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • PD1 Monoclonal Antibody
  • IAP Antagonist

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